| Structural highlights
8vrn is a 9 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | Electron Microscopy, Resolution 2.57Å |
| Ligands: | , , , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
GBRB2_HUMAN Component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the vertebrate brain. Functions also as histamine receptor and mediates cellular responses to histamine. Functions as receptor for diazepines and various anesthetics, such as pentobarbital; these are bound at a separate allosteric effector binding site. Functions as ligand-gated chloride channel.[1] [2]
Publication Abstract from PubMed
Methaqualone, a quinazolinone marketed commercially as Quaalude, is a central nervous system depressant that was used clinically as a sedative-hypnotic, then became a notorious recreational drug in the 1960s-80s. Due to its high abuse potential, medical use of methaqualone was eventually prohibited, yet it persists as a globally abused substance. Methaqualone principally targets GABA(A) receptors, which are the major inhibitory neurotransmitter-gated ion channels in the brain. The restricted status and limited accessibility of methaqualone have contributed to its pharmacology being understudied. Here, we use cryo-EM to localize the GABA(A) receptor binding sites of methaqualone and its more potent derivative, PPTQ, to the same intersubunit transmembrane sites targeted by the general anesthetics propofol and etomidate. Both methaqualone and PPTQ insert more deeply into subunit interfaces than the previously-characterized modulators. Binding of quinazolinones to this site results in widening of the extracellular half of the ion-conducting pore, following a trend among positive allosteric modulators in destabilizing the hydrophobic activation gate in the pore as a mechanism for receptor potentiation. These insights shed light on the underexplored pharmacology of quinazolinones and further elucidate the molecular mechanisms of allosteric GABA(A) receptor modulation through transmembrane binding sites.
Structural insights into GABA(A) receptor potentiation by Quaalude.,Chojnacka W, Teng J, Kim JJ, Jensen AA, Hibbs RE Nat Commun. 2024 Jun 19;15(1):5244. doi: 10.1038/s41467-024-49471-y. PMID:38898000[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Zhao C, Xu Z, Wang F, Chen J, Ng SK, Wong PW, Yu Z, Pun FW, Ren L, Lo WS, Tsang SY, Xue H. Alternative-splicing in the exon-10 region of GABA(A) receptor beta(2) subunit gene: relationships between novel isoforms and psychotic disorders. PLoS One. 2009 Sep 18;4(9):e6977. doi: 10.1371/journal.pone.0006977. PMID:19763268 doi:http://dx.doi.org/10.1371/journal.pone.0006977
- ↑ Hadingham KL, Wingrove PB, Wafford KA, Bain C, Kemp JA, Palmer KJ, Wilson AW, Wilcox AS, Sikela JM, Ragan CI, et al.. Role of the beta subunit in determining the pharmacology of human gamma-aminobutyric acid type A receptors. Mol Pharmacol. 1993 Dec;44(6):1211-8. PMID:8264558
- ↑ Chojnacka W, Teng J, Kim JJ, Jensen AA, Hibbs RE. Structural insights into GABA(A) receptor potentiation by Quaalude. Nat Commun. 2024 Jun 19;15(1):5244. PMID:38898000 doi:10.1038/s41467-024-49471-y
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